Composition and method for treatment of depression and psychosis in humans

ABSTRACT

Compositions and methods for the treatment of depression and psychoses in humans are disclosed. More particularly, the invention is directed to formulations containing antipsychotic and/or antidepressant medications and also containing an NMDAR antagonist. The present Invention Is also directed to methods tor the treatment of humans suffering from depression and other psychoses, including, schizophrenia, by administration of the inventive compositions in antidepressant and/or antipsychotic effective amounts.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional of co-pending U.S. patent application Ser. No.13/936,198, filed Jul. 7, 2013, which claims the benefit of provisionalapplication No. 61/741,114, filed Jul. 12, 2012, and provisionalapplication No. 61/741,115, filed Jul. 12, 2012, the contents of each ofwhich are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Schizophrenia is a clinical syndrome associated with psychotic symptomssuch as delusions and hallucinations, as well as a decline in functionin such areas as work, social relation or self care.

Diagnosis of schizophrenia may be determined using standard textbooks ofthe art, such as the Diagnostic and Statistical Manual of MentalDisorders-fourth edition (DSM-IV) published by the American PsychiatricAssociation. Symptoms of schizophrenia are typically measured usingrating scales such as the Positive and Negative Syndrome Scale (PANSS).

Symptoms of schizophrenia are treated with antipsychotic medications,which function primarily by blocking dopamine D2 receptors.

Antipsychotics may be divided into typical (e.g. chlorpromazine,haloperidol. perphenazine) vs. atypical (e.g. amisulpride, aripiprazole,asenapine, bioanserin, bifeprunox, cariprazine, clotiapine, clozapine,iloperidone, lurasidone, mosaproamine, olanzapine, paliperidone,perospirone, quetiapine, remoxipride, risperidone, sertindole,sulpiride, ziprasidone, zotepine) based upon receptor binding,preclinical effects and side effect profile. Clinically effective dosesof antipsychotic medication typically produce >60% occupancy of dopamineD2 receptors. Atypical antipsychotics may be partial or full D2antagonists and may also have activity at additional catecholamine andserotonin receptor types, including 5-HT2A and 5-HT2C receptors andadrenergic alpha1 and alpha2 receptors. Atypical antipsychotics may alsoaffect other receptor types, such as such as muscarinic cholinergicreceptors.

Major depression is a clinical syndrome that includes a persistent sadmood or loss of interest in activities, which persists for at least twoweeks in the absence of treatment. Symptoms of major depression aretypically measured using rating scales such as the Hamilton DepressionRating Scale (HAM-D) or the Beck Depression inventory (BDI). In additionto including symptoms relevant to depressed mood, the HAM-D alsocontains symptoms sensitive to psychosis, including items for guilt,depersonalization/derealization and paranoia. Major depression may alsobe associated with symptoms of anxiety, which may be measured withrating scales such as the Hamilton Rating Scale for Anxiety (HAM-A).Depressive disorders are divided in major depression (MDD) and bipolardepression (BPD), which may be diagnosed using criteria set forth in theDiagnostic and Statistical Manual, 4th edition, published by theAmerican Psychiatric Association (DSM-IV), which provides as welladditional description of mental disorders. Major depression may alsooccur with and without melancholic features. In addition, depressivesymptoms may occur in the context of anxiety disorders such asgeneralized anxiety disorder, dissociative disorders, personalitydisorders or adjustment disorders with depressed mood (DSM-IV).

Current treatments for major depression consist primarily of olderantidepressants, such as monoamine oxidase inhibitors (MAOI) andtricyclic antidepressants (TCAs) (e.g. imipramine, amitryptiline,desipramine, clomipramine) that were first developed in the 1960's, andnewer agents such as tetracyclic antidepressants (TeCAs), e.g.amoxapine, setiptiline, maprotiline, mianserin, mirtazapine), serotonin(SSRI) and serotonin/norephinephrine (SNRI) reuptake inhibitors (e.g.,fluoxetine, fluvoxamine, paroxetine, citalopram, escitalopram,duloxetine, venlafaxine, dapoxetine, indalpine, valzodone). These agentswork by modulating brain levels of monoamines, in particularnorepinephrine and serotonin, and/or by blocking 5-HT2A receptors. MAOIsand TCAs are considered “broader spectrum” agents than SSRIs/SNRIs thatwere developed subsequently MAOI, TCAs, TeCAs, SSRIs, and SNRIs maycollectively be considered traditional antidepressants.

Antipsychotics may also be effective in treatment of depression.Potentially beneficial antipsychotic medications include but are notlimited to risperidone, olanzapine, quetiapine, aripiprazole, clozapine,iloperidone, sertindole, asenapine, lurasidone, cariprazine.

Other antipsychotics and antidepressants in development include Valdoxan(agomelatine, AG0178) (Servier, Novartis), Lu AA21004 (Lundbeck,Takeda), F2695, levomilnacipran (Forest, Pierre Fabre), SEP-227162(Sepracor), LuAA24530 (Lundbeck, Takeda). SEP-225289 (Sepracor),Epivanserine (Sanofi-Aventis), SR463 9 (Sanofi-Aventis). LY12624803,HY10275 (Lilly, Hypnion), TI-301/LY156735 (Tikvah Therapeutics), Lonasen(bioanserin, Dainippon), LU-31-130 (Lundbeck), SLV313 (Solvay).Edivoxetine (LY2216684, Lilly), OPC-34712 (Otsuka/Lundbeck), Vyvanse(lisdexamfetamine, Shire), BCI-224 (sacomeline, BrainCells), BCI-540(clouracetam, BrainCells), BMS-82036 (BMS/AMRI).

However, current treatment approaches have severe limitations. Only60-65% of patients respond to the initial regimen and among thoseresponding, less than half either reach remission or becomesymptom-free. Individuals not responding to a first course ofantidepressant treatment are often switched to a different drug, withresults that are generally modest and incremental.

5-HT2A receptors are a type of receptor for the neurotransmitterserotonin. 5-HT2A antagonists are compounds that inhibit effects ofagonists such as serotonin on 5-HT2A receptors. Inverse agonists arecompounds that, in addition, reduce activity below basal levels. 5-HT2Areceptor antagonists can be non-selective for 5-HT2A vs. other serotoninreceptors (e.g. 5-HT2C), or selective for 5-HT2A receptors. Selective5-HT2A antagonists can be developed and characterized using standardassay procedures, such as those described in U.S. Pat. No. 7,713,995issued on May 11, 2010, which is herein incorporated by reference in itsentirety.

Agents that act as non-selective serotonin receptor antagonists includeritanserin. ketanserin, seganserin, and ICI-169369. Agents that act asselective 5-HT2A antagonists or inverse agonists include volinanserin(MDL100.907, also known as M100907), pruvanserin (EMD281014),eplivanserin, CYR-101 and pimavanserin (ACP-103). Selective 5-HT2Areceptor antagonists and inverse agonists are presently underdevelopment for treatment of both depression and psychosis and areviewed as potential antidepressant/antipsychotic agents.

Additional 5-HT2A receptor antagonists or inverse agonists are describedin U.S. Pat. No. 7,875,632 which was issued on Jan. 25, 2011; U.S. Pat.No. 7,868,176 issued on Jan. 11, 2011; U.S. Pat. No. 7,863,296 issued onJan. 4, 2011; U.S. Pat. No. 7,820,695 issued Oct. 26, 2010; and/or U.S.Pat. No. 7,713,995 issued May 11, 2010 which are herein incorporated byreference in its entirety.

Treatment-refractory depression refers to a form of depression thatresponds poorly to currently available treatments (e g,http://www.nimh.nih.gov/trials/practical/stard/index.shtml June 2011)and which may have different underlying etiopathological mechanismscompared with other forms of depression. Combinations of antidepressantshave not been shown to be superior to monotherapy for refractorydepression and typically increase risk of side effects and are notrecommended.

Risk for suicide is significantly increased in depressive disorders, butmay respond differentially to medication versus depressive symptoms as awhole. When suicide occurs, it is often accompanied by feelings ofworthlessness or inappropriate guilt, as well as recurrent thoughts ofdeath or suicidal ideation and guilt is an accepted proxy for suicide.While the risk of suicide increases in subjects with a depressivedisorder, medications used to date to typically treat depressivedisorders paradoxically increase suicidal tendencies.

A major limitation in use of antipsychotic and antidepressantmedications is the liability to produce behavioral side effects,especially anxiety, agitation, and akathisia. These can bedifferentiated from symptoms of the illness by consideration of bothtime course and specific patterns of symptoms.

In addition to akathisia, antipsychotics also produce extrapyramidalsymptoms such as stiffness, tremor or dyskinesia. Akathisia, however, isdifferentiated from extrapyramidal symptoms and shows differentialtreatment response. At present, there are no approved treatments forantipsychotic-induced akathisia.

Use of antidepressants is also limited by liability to produce anxiety,agitation, and akathisia.

Limitations of antidepressants are summarized in a “black box” warningrequired by the FDA, as follows: The following symptoms, anxiety,agitation, panic attacks, insomnia, irritability, hostility,aggressiveness, impulsivity, akathisia (psychomotor restlessness),hypomania, and mania have been reported in adult and pediatric patientsbeing treated with antidepressants for major depressive disorder as wellas for other indications, both psychiatric and non-psychiatric. Althougha causal link between the emergence of such symptoms and either theworsening of depression and/or the emergence of suicidal impulses hasnot been established, there is concern that such symptoms may representprecursors to emerging suicidality” (Trivedi et al., J Olin Psychiatry.72.765-774. 2011).

As with antipsychotic-induced akathisia, there are at present no knowntreatments for antidepressant induced anxiety, agitation, or akathisia.

Anxiety and akathisia may be studied in animal models, such as the ratdefection or restlessness models, as described, for example, in Schdev &Brune, Animal models of acute drug-induced akathisia—a review. NeurosciBiobehav Rev 24:269-277. 2000).

Antipsychotics and antidepressants, including 5-HT2A receptorantagonists, may also be used therapeutically in the treatment ofbipolar disorder (manic depressive psychosis), Alzheimers disease,Parkinsons disease, dementia, anxiety disorders, pain and developmentaldisorders including autism.

N-methyl-D-aspartate receptors (NMDAR) are a type of receptor for thebrain neurotransmitter glutamate. NMDAR participate in a range of brainfunctions including sensory processing, cognition, and emotionregulation.

NMDAR are comprised of multiple subunits termed GluN1, GluN2 and GluN3(formerly NR1, NR2, NR3). Multiple forms of GluN1, GluN2 and GluN3exist. In particular, GluN2 subunits are divided into GluN2A-D subforms,which are also termed NR2A-D subunits. NMDAR may consist of variouscombinations of GluN1, GluN2 and GluN3 subunits in various amounts.Agonists and antagonists may affect all NMDAR equivalently, or may beselective for NMDAR containing specific subunit types.

NMDAR contain binding sites for both the neurotransmitter glutamate andfor the endogenous modulatory amino acids glycine and D-serine.

The glutamate binding site also selectively binds the syntheticglutamate derivative N-methyl-D-aspartate with high affinity. This siteis alternately referred to as the glutamate recognition site of the NMDArecognition site of the NMDAR.

The glycine/D-serine binding site has been referred to as the glycinemodulatory site, the allosteric modulatory site or the glycine-Breceptor.

NMDAR form an ion channel that is blocked by several drugs of abuse,such as phencyclidine (PCP), ketamine or dizocilpine (MK-801). Thesecompounds bind to a site that has been termed the PCP receptor. Agentsthat block the NMDAR-associated ion channel are collectively termednoncompetitive NMDAR antagonists, or NMDAR channel blockers. Blockade ofNMDAR by channel blockers leads to a clinical psychotic state thatclosely resembles schizophrenia.

Other compounds that block NMDA receptors via the channel site includeAZD6765 (AstraZeneca) and Glyx-13 (Naurex). NRX-1059 (Naurex)

Other NMDAR antagonists are described in U.S. Patent appl. #20110306586published Dec. 15. 2011, which is herein incorporated by reference inits entirety.

Low affinity NMDAR antagonists, such as memantine, may be distinguishedfrom high affinity antagonists such as PCP, ketamine or dizocilpine. Ingeneral, low affinity NMDAR antagonists do not induce schizophrenia-likepsychosis or PCP-like behavioral effects in rodents.

NMDAR may also be inhibited by antagonists that bind to the glutamaterecognition sites, the glycine recognition site, or the channel bindingsite.

Selfotel (CGS19755) is an example of an antagonist that binds to theglutamate recognition site. Several such compounds were developed forCNS indications such as stroke or epilepsy. When used at dosessufficient to significantly inhibit NMDAR, these compounds, like channelblockers, lead to clinical psychotomimetic symptoms.

Additional compounds that functions as antagonists of the glutamaterecognition site include aptiganel (Cerestat, CNS-1102) and relatedcompounds as described in Reddy et al., J Med Chem 37:260-7. 1994.

Additional compounds that function as antagonists of the glutamaterecognition site include alpha.-amino-carboxylic acid and phosphonicacid functionalities separated by a variety of spacer units. Anunembellished example is 2-amino-5-phosphonovaleric acid (AP5) (Watkins,J. C; Evans, R. H., Annu. Rev. Pharmacol. Toxicol. 1981, 21, 165), whichcontains a saturated carbon chain. More complex examples, which containelements enhancing structural rigidity and therefore potency, includeCPP, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid (CGS-19755)(Lehman, J. et al., J. Pharmacol. Exp. Ther. 1988, 246, 65), and(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP-37849) (Schmutz,M. et al., Abs. Soc. Neurosci. 1988, 14. 864). See U.S. Pat. No.7,345,032, issued Mar. 18, 2008 and U.S. Pat. No. 5,168,103,incorporated herein by reference in its entirety.

NMDAR may also be inhibited by antagonists that bind to the glycinerecognition site.

D-cycloserine is a compound that acts as a partial glycine-siteantagonist. D-cycloserine doses may be divided into low doses (0-250mg), moderate (≧250-500 mg) or high (≧500 mg). At low dose,D-cycloserine may function as a net NMDAR agonist. At high doses,D-cycloserine may function as a net NMDAR antagonist. Plasmaconcentrations associated with moderate or high dose administrationare >25 microgram/ml.

Felbamate is another example of a compound that may act via the glycinebinding site. When administered to humans, felbamate produces psychoticeffects that limit its clinical utility (e.g. Besag F M, Expert OpinDrug Saf 3:1-8, 2004).

Gavestinel (GV-150,526) is another example of a glycine binding siteantagonist. Other compounds are described in DiFabrio et al., J Med Chem40:841-50, 1997. which is hereby incorporated by reference.

Other examples of glycine site antagonists that are suitable for use inthe pharmaceutical compositions and methods of this invention are thosereferred to in the following: U.S. Pat. No. 6,667,317 which was issuedon Dec. 23, 2003; U.S. Pat. No. 6,080,743 which was issued Jun. 27,2000; U.S. Pat. No. 5,990,108, which was issued on Nov. 23, 1999; U.S.Pat. No. 5,942,540, which issued on Aug. 24, 1999; World PatentApplication WO 99/34790 which issued on Jul. 15. 1999; WO 98/47878,which was published on Oct. 29, 1998; World Patent Application WO98/42673, which was published on Oct. 1. 1998; European PatentApplication EP 966475A1, which was published on Dec. 29, 1991; WorldPatent Application 98/39327, which was published on Sep. 11, 1998; WorldPatent Application WO 98/04556, which was published on Feb. 5, 1998;World Patent Application WO 97/37652, which was published on Oct. 16.1997; U.S. Pat. No. 5,837,705, which was issued on Oct. 9, 1996; WorldPatent Application WO 97/20553, which was published on Jun. 12, 1997;U.S. Pat. No. 5,886,018, which was issued on Mar. 23, 1999; U.S. Pat.No. 5,801,183. which was issued on Sep. 1, 1998, World PatentApplication WO 95/07887, which was issued on Mar. 23, 1995; U.S. Pat.No. 5,686,461, which was issued on Nov. 11, 1997; U.S. Pat. No.5,622,952, issued Apr. 22, 1997; U.S. Pat. No. 5,614,509, which wasissued on Mar. 25, 1997; U.S. Pat. No. 5,510,367, which was issued onApr. 23, 1996; European Patent Application 517.347A1, which waspublished on Dec. 9. 1992; U.S. Pat. No. 5,260,324, which published onNov. 9. 1993. The foregoing patents and patent applications areincorporated herein by reference in their entireties.

Other examples of glycine site antagonists that can be used in thepharmaceutical composition and methods of this invention areN-{6,7-dichloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl)-N-(2-hydroxy-ethyl)-methanesulfonamideand6,7-dichloro-5-[3-methoxymethyl-5-(1-oxypyridin-3-yl)-[1,2,4]triazol-4-yl]-1,4-dihydro-quinoxa-line-2,3-dione.

Additional NMDAR antagonists are described in Schiene et al., U.S. Pat.Appl. No. US2001/0306674 A1, which is incorporated herein by referencein its entirety, and include without being limited thereto, N-containingphosphonic acids, such as norvaline (AP5), D-norvaline (D-AP5),4-(3-phosphono-propyl)-piperazine-2-carboxylic acid (CPP),D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D-CPPene),cis-4-(phosponometyl)-2-piperidine carboxylic acid (Selfotel, CGS19755), SDZ-220581, PD-134705, LY-274614 and WAY-126090; quinolinicacids, such as kynurenic acid, 7-chloro-kynurenic acid,7-chloro-thiokynurenic acid and 57-dichloro-kynurenic acid, prodrugsthereof, such as 4-chlorokynurenine and 3-hydroxy-kynurenine;4-aminotetrahydrochinolin-carboxylates, such as L-689,560;4-hydroxyquinolin-2(1H)-ones, such as L-701,324; quinoxalinediones. suchas Itcostinel (ACEA-1021) and CGP-68.730A;4,6-dichloro-indole-2-carboxylate derivatives such as MDL-105,519,gavestinel (GV-150.526) and GV-196.771A; tricyclic compounds, such asZD-9,379 and MRZ-2/576, (+)-HA-966, morphinan derivatives such asdextromethorphan and dextrophan; benzomorphans, such as BIII-277CL;other opioids, such as dextropropoxyphene, ketobemidone, dextromethadoneand D-morphine; amino-adamantanes, such as amantadine and memantine;amino-alkyl-cyclohexanes, such as MRZ-2 579; ifenprodil andifenprodile-like compounds such as eliprodil and PD-196,860;iminopyrimidines; or other NMDA-antagonists such as nitroprusside,D-cycloserine. 1-aminocyclopropane-carboxylic acid, dizocilpine (MK 801)and its analogs, phencyclidine (PCP), ketamine((R.S)-2-(2-Chlorphenyl)-2-(methylamino)cyclohexan-1-on), (R)-ketamine,(S)-ketamine, remacemide and its des-glycinyl-metabolite FPL-12.495,AR-R-15,896, methadone, sulfazocine, A 19/AVex-144, AN2/AVex-73,Besonprodil, CGX-1007, EAB-318. Felbamate and NPS-1407. N DA-Antagonistsare, for example, disclosed in “Analgesics,” edited by H. Buscmann, T.Christoph, E. Friderichs, C. Maul, B. Sundermann, 2002, Wiley-VCH VerlagGmbH & Co. KGaA, Weinheim, Germany, in particular pages 389-428. Therespective parts of the description are hereby incorporated by referenceand form part of the present disclosure.

Antagonists may be selective for the GluN2B (NR2B) containing subtype.Examples of compounds that are selective for NR2B containing receptorsinclude ifenprodil, traxoprodil (CP-101.606). besonprodil, Ro25-6981MK-0657 and EVT-101.

Along with identified NMDAR antagonists, additional can be identifiedusing well-validated electrophysiological assays such as modulation ofNMDA-receptor mediated responses to NMDA glutamate-site agonists, orradioreceptor assays, such as modulation of binding to the NMDAPCP-receptor channel binding site. Glycine site agonists and antagonistscan also be distinguished based upon both electrophysiology and receptorbinding from compounds such as phencyclidine (PCP) or ketamine that bindto the channel site. Partial agonists are defined as compounds that havereduced efficacy for inducing conformational change in receptors(typically 40-80%) relative to full agonists, and which may induceagonist effects at low dose but antagonist effects at high dose.

The NMDAR antagonist ketamine is currently approved as an anestheticagent. It has also been reported to show beneficial effects in treatmentresistant depression in small scale clinical trials. However, itsutility is limited by psychotomimetic effects. The low affinity NMDARantagonist memantine is approved for use in dementia. Otherwise, NMDARantagonists have no established clinical utility.

In general, NMDAR antagonists are considered contraindicated for use inschizophrenia or depression. For example, the NMDAR antagonistD-cycloserine is contraindicated by FDA for use in depression, severeanxiety or psychosis.

Here we show unexpectedly that NMDAR antagonists unexpectedly reduceakathisia and anxiety associated with antidepressant and/orantipsychotic treatment.

Here we show unexpectedly that antidepressants prevent psychoticsymptoms associated with NMDAR agonist usage.

These findings provide a method for improved treatment of humansrequiring treatment with an antipsychotic, antidepressant, or NMDARantagonist medication.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graphical representation of the results described in theExample described hereinafter showing the percent of time spent in theopen arms of the testing device for very drugs or combination of drugs.

SUMMARY OF THE INVENTION

The present invention is directed towards compositions for the treatmentof depression and psychoses in humans. More particularly, the inventionis directed to formulations containing antipsychotic and orantidepressant medications including selective 5-HT2A receptorantagonists/inverse agonists and also containing an NMDAR antagonist.The present invention is also directed to methods for the treatment ofhumans suffering from depression and other psychoses, including,schizophrenia, by administration of the inventive compositions inantidepression and/or antipsychotic effective amounts.

In one embodiment, this invention provides an oral or parenteral dosageregimen consisting essentially of two therapeutic agents, wherein afirst of said two active ingredients is an antidepressant orantipsychotic agent, and the second agent consists of an NMDAR receptorantagonist.

In some embodiments of the invention, the first compound consists of atypical or atypical antipsychotic agent

In some embodiments of the invention, the first therapeutic agent isdrawn from a list that includes amisulpride, aripiprazole, asenapine,bifeprunox, bioanserin, cariprazine, clotiapine, clozapine, iloperidone,lurasidone, mosaproamine, olanzapine, palipendone, perospirone,quetiapine, remoxi pride, risperidone, sertindole, sulpiride,ziprasidone, zotepine.

In some embodiments, the first therapeutic agent comprises a tetracyclicantidepressant (TeCA), selective serotonin reuptake inhibitor (SSRI), aserotonin/norephinephrine reuptake inhibitor (SNRI)a 5-HT2Aantagonist/inverse agonist or a combination thereof.

5-HT2A receptor antagonists/inverse agonists may be drawn from a listthat includes volinanserin (MDL 100.907, also known as M100907)pruvanserin (EMD281014), eplivanserin, CYR-101 and pimavanserin(ACP-103).

NMDAR antagonists may be drawn from antagonists at the glycine,glutamate or channel recognition sites.

NMDAR antagonists may be non-selective antagonists or selectiveantagonists at NMDAR containing specific subunits such as the NR2A orNR2B subunits.

In some embodiments of the invention, the antidepressant may be selectedfrom the group consisting of includes imipramine, amitryptiline,desipramine, clomipramine, amoxapine, setiptiline, maprotiline,mianserin, mirtazapine, fluoxetine, fluvoxamine, paroxetine, citalopram,escitalopram, duloxetine, venlafaxine. dapoxetine, indalpme, valzodone.

In some embodiments of the invention, the first therapeutic agent isdrawn from a list that includes agomelatine, Lu AA21004, F2695,levomilnacipran, SEP-227162, LuAA24530, SEP-225289, Epivanserine,SR46349, LY12624803, HY10275, TIK-301/LY156735, Lonasen, LU-31-130.SLV313, Edivoxetine, OPC-34712, lisdexamfetamine, sacomeline,clouracetam, and BMS-82036.

In some embodiments, the second therapeutic agent is drawn from a listthat includes ketamine, dextromethorphan, CNS-1 102.AZD6765 orCGS-19755.

In a preferred embodiment of the invention, the second therapeutic agentconsists of D-cycloserine, administered at a dosage of at least 500 mgper day.

In some embodiments, the NMDA receptor antagonists consists ofD-cycloserine, administered at a dose that produces serum levels inexcess of 25 microgram/mL.

In some embodiments, this invention provides a method for treatment of apsychosis in a subject in need thereof, said method comprising providingsaid subject with an oral or parenteral dosage regimen as hereindescribed.

In some embodiments, this invention provides a method for treatment ofdepression in a subject in need thereof, said method comprisingproviding said subject with an oral or parenteral dosage regimen asherein described.

In some embodiments, the subject suffers from mania, or in someembodiments, the subject suffers from bipolar disorder.

In some embodiments, this invention provides a method for treatingsymptoms of autism in a subject in need thereof, said method comprisingproviding said subject with an oral or parenteral dosage regimen asherein described.

In some embodiments, the invention provides a method for reducing sideeffects associated with antipsychotic medications to a subject in needof such treatment, said method comprising providing said subject with anoral or parenteral dosage regimen as herein described.

In some embodiments, this invention provides a method for reducing sideeffects associated with antidepressant medications to a subject in needof such treatment, said method comprising providing said subject with anoral or parenteral dosage regimen as herein described.

In some embodiments, this invention provides a method for reducing sideeffects associated with NMDAR antagonist medications to a subject inneed of such treatment, said method comprising providing said subjectwith an oral or parenteral dosage regimen as herein described.

In some embodiments, a gelling agent such as hydroxypropylmethylcellulose, together with one or more pharmaceutically acceptableexcipients is used for manufacture of the sustained release agent.

In some embodiments, the sustained release formulation comprises ahydrophilic matrix comprising a gelling agent, preferably hydroxypropylmethylcellulose, an NMDA receptor antagonist, an antidepressant andpharmaceutically acceptable salts thereof, together with one or morepharmaceutically acceptable excipients.

In some embodiments both the NMDA receptor antagonist and theantidepressant or antipsychotic medication would be manufactured forsustained release in common.

In some embodiments, the NMDA receptor antagonist would be manufacturedfor sustained release, and combined with an antidepressant orantipsychotic agent.

In some embodiments, the antidepressant or antipsychotic agent would bemanufactured for sustained release, and combined with an NMDA receptorantagonist.

In one embodiment, an NMDA receptor antagonist and an antidepressant orantipsychotic agent would be selected for release characteristicspermitting once daily dosing of the combined medicament, and would notrequire separate sustained release manufacture.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides, in some embodiments, parenteral or intravenousdosage regimens, which are useful in the treatment of schizophrenia ordepression in a subject in need thereof, or in the reduction of theincidence or akathisia or anxiety in a subject or population in needthereof.

In some embodiments, the invention provides an oral or parenteral dosageregimen consisting essentially of two active ingredients, wherein afirst of said ingredients is an antipsychotic or antidepressant agent.

In some embodiments, according to this aspect, the first therapeuticagent comprises any such agent as herein described, for example, atetracyclic antidepressant (TeCA), selective serotonin reuptakeinhibitor (SSRI), a serotonin/norephinephrine reuptake inhibitor (SNRI),a selective 5-HT2A receptor antagonist, a selective 5-HT2A receptorinverse agonist, an antipsychotic approved for use in treatment ofdepression or a combination thereof.

In some embodiments, the selective 5-HT2A antagonist/inverse agonist isselected from the group consisting of volinanserin (MDL100.907, M100907)pruvanserin (EMD281014), eplivanserin, CYR-101 and pimavanserin(ACP-103).

In some embodiments, the first therapeutic agent is an antipsychoticagent, consisting of a typical or atypical antipsychotic.

In some embodiments, the antipsychotic agent is selected from the groupconsisting of amisulpride, aripiprazole, asenapine, bioanserin,bifeprunox, cariprazine, clozapine, clozapine, iloperidone, lurasidone,mosaproamine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone, zotepine.

In some embodiments, the second therapeutic agent is an NMDARantagonist.

In some embodiments, the second therapeutic agent acts at the glycine,glutamate or channel recognition sites.

In some embodiments, the second therapeutic agent acts at NMDARcontaining NR2A subunits.

In some embodiments, the second therapeutic agent acts at NMDARcontaining NR2B subunits.

In some embodiments, the second therapeutic agent is drawn from a listthat includes ketamine, Selfotel, aptiganel, CPP, CGP-37849, felbamate,GavestinelN-(6,7-dichloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl)-N-(2-hydroxy-ethyl)-methanesulfonamideand6,7-dichloro-5-[3-methoxymethyl-5-(1-oxypyridin-3-yl)-[1,2.4]triazol-4-yl]-1,4-dihydro-quinoxa-line-2,3-dione,4-(3-phosphono-propyl)-piperazine-2-carboxylic acid (CPP),D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D-CPPene),SDZ-220581, PD-134705.LY-274614 and WAY-126090; quinolinic acids, suchas kynurenic acid, 7-chloro-kynurenic acid, 7-chloro-thiokynurenic acidand 5,7-dichloro-kynurenic acid, prodrugs thereof, such as4-chlorokynurenine and 3-hydroxy-kynurenine;4-aminotetrahydrochinolin-carboxylates, such asL-689.5604-hydroxyquinolin-2(1H)-ones, such as L-701,324;quinoxalinediones, such as licostinel (ACEA-1021) and CGP-68.730A;4,6-dichloro-indole-2-carboxylate derivatives such as MDL-105,519,gavestinel (GV-150,526) and GV-196.771A; tricyclic compounds, such asZD-9,379 and MRZ-2/576, (+)-HA-966, morphinan derivatives such asdextromethorphan and dextrophan; benzomohans, such as BIII-277CL; otheropioids, such as dextropropoxyphene, ketobemidone, dextromethadone andD-morphine; amino-adamantanes, such as amantadine and memantine;amino-alkyl-cyclohexanes, such as MRZ-2579; ifenprodil andifenprodile-li e compounds such as eliprodil and PD-196,860;iminopyrimidines; or other NMDA-antagonists such as nitroprusside,D-cycloserine, 1-aminocyclopropane-carboxylic acid, dizocilpine (MK 801)and its analogs, (R)-ketamine, (S)-ketamine, remacemide and itsdes-glycinyl-metabolite FPL-12,495, AR-R-15,896, methadone, sulfazocine,A 19/AVex-144, AN2/AVex-73, Besonprodil, CGX-1007.EAB-318, and NPS-1407.

In some embodiments, the second compound is D-cycloserine, administeredat a dose of 500 mg or greater.

In some embodiments, the two active ingredients are provided in a singlepharmaceutical composition, and in some embodiments, the inventioncontemplates a kit or combined dispenser packet containing each of thetwo active ingredients.

It is to be understood that the invention contemplates theco-administration of either of the two active ingredients to a subject,whether such administration is combined in a single formulation or inseparate formulations and whether such administration is coincident orstaggered.

The inventive composition may be administered by a variety ofwell-established medicinal routes including intravenously,intraperitoneally, parentally, intramuscularly, or orally.

In some embodiments, this invention provides a method for treatingdepression in a subject in need thereof, said method comprisingadministering an effective amount of the inventive composition in theform of an oral or parenteral dosage or a parenteral injection as hereindescribed.

In some embodiments, the subject suffers from schizophrenia, or in someembodiments, the subject suffers from bipolar disorder. In someembodiments, the invention provides a method for reducing the incidenceor treating suicide or suicide ideation in a subject or population inneed thereof, the method comprising providing the subject with an oralor parenteral or parenteral dosage regimen as herein described.

In some embodiments, reference to an “effective” amount or a“therapeutically effective amount” of therapeutic agents referencedherein, it is meant a nontoxic but sufficient amount of the same toprovide the desired effect. In a combination therapy of the presentinvention, an “effective amount” of one component of the combination isthe amount of that compound that is effective to provide the desiredeffect when used in combination with the other components of thecombination. The amount that is “effective” will vary from subject tosubject, depending on the age and general condition of the individual,the particular active agent or agents, and the like. Thus, it is notalways possible to specify an exact “effective amount” However, anappropriate “effective” amount in any individual case may be determinedby one of ordinary skill in the art using routine experimentation

The terms “treating” and “treatment” as used herein refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, prevention of the occurrence of symptoms and/or theirunderlying cause, and improvement or remediation of damage. Thus, forexample, “treating” a patient involves prevention of a particulardisorder or adverse physiological event in a susceptible individual aswell as treatment of a clinically symptomatic individual.

D-cycloserine, or DOS, refers to the chemical D-cycloserine (CA IndexName.3-Isoxazolidinone, 4-amino-, (4R)-(9Cl); CAS Registry No. 68-41-7),or pharmaceutically acceptable salts thereof. DOS is an FDA (UnitedStates Food and Drug Administration)-approved drug for treatment oftuberculosis, and is sold by Eli Lilly and Company under the trade nameSeromycin®DCS is a structural analog of D-alanine, and is abroad-spectrum antibiotic produced by some strains of Streptomycesorchidaceus and S. garphalus. In some embodiments, the inventivecombination may be used in the treatment of tuberculosis.

Indicia is provided and disposed adjacent the columns and rows fordisplaying common days and successive weeks. Thus, the package providesfor a titration schedule which prevents adverse events as a result ofmis-dosing. As a result, the package in accordance with the presentinvention provides for a safer and accordingly more beneficial methodfor enabling compliance with the regimen.

In some embodiments, according to this aspect, the first therapeuticagent is administered at a dosage, which is considered to be suboptimalfor treating depression or psychosis in said subject when treating saidsubject with said first therapeutic agent alone.

A subject undergoing treatment with the methods of the invention canexperience significant improvements in depression. Relative to subjectstreated with alternative treatments for depression, subjects treatedaccording to the methods of the invention will experience, in someembodiments, greater improvement, or more long-lasting improvement, asmeasured by any clinically recognized assessment method for depression(e.g., the 21-item Hamilton Depression Rating Scale). It should be notedthat not every subject will benefit from the methods of the invention,just as other pharmaceutical agents do not typically benefit everypatient.

A subject undergoing treatment with the methods of the invention canexperience significant improvements in anxiety. Relative to subjectstreated with alternative treatments for anxiety, subjects treatedaccording to the methods of the invention will experience, in someembodiments, greater improvement, or more long-lasting improvement, asmeasured by any clinically recognized assessment method for anxiety(e.g., the Hamilton Anxiety Rating Scale). It should be noted that notevery subject will benefit from the methods of the invention, just asother pharmaceutical agents do not typically benefit every patient

A subject undergoing treatment with the methods of the invention canexperience significant improvements in akathisia. Relative to subjectstreated with alternative treatments for akathisia, subjects treatedaccording to the methods of the invention will experience, in someembodiments, greater improvement, or more long-lasting improvement, asmeasured by any clinically recognized assessment method for akathisia(e.g, the Barnes Akathisia Rating Scale). It should be noted that notevery subject will benefit from the methods of the invention, just asother pharmaceutical agents do not typically benefit every patient.

A subject undergoing treatment with the methods of the invention canexperience significant improvements in psychosis. Relative to subjectstreated with alternative treatments for psychosis, subjects treatedaccording to the methods of the invention will experience, in someembodiments, greater improvement, or more long-lasting improvement, asmeasured by any clinically recognized assessment method for psychosis(e.g., the Positive and Negative Symptom Scale). It should be noted thatnot every subject will benefit from the methods of the invention, justas other pharmaceutical agents do not typically benefit every patient.

EXAMPLE Example Effect of NMDAR Antagonists on Akathisia Induced by5-HT2A Antagonists

Background: Drug induced akathisia is a common side effects of bothantipsychotic and antidepressant medication and may be seen even withnewer atypical antipsychotics (Iqbal et al., CNS Spectrums, 12:1-13,2007). This syndrome has also been described as anxiety/jitterinesssyndrome (Sinclair et al., Br J Psychiatry, 194:483-90, 2009), which isalso seen following both SSRIs and tricyclic antidepressants.

Although no exact animal models exist at present, rodent activitymeasures which asses partial restlessness have been proposed to haveface validity (Sachdev and Brune. Neurosci Biobehav Rd 24:269-277,2000), justifying their use. Agonists at the 5-HT2A receptor, such as(+/−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) have welldescribed anxiolytic properties that may be detected in rodent assayssuch as the four-plate test or the elevated plus maze (Nic Dhonnchadhaet al Behavioural brain research. 147:175-84, 2003). Effects of 5-HT2Aligands may be mediated in part via the GABA system (Masse et al., BehavBrain Res 177:214-26. 2007), increasing the relevance of this mechanismsfor akathisia

The present investigation tests the hypothesis that NMDA receptorantagonists may reverse the akathasia-induced effects of agents thatwork in whole or in part through 5-HT2A blockade, including selective5-HT2A antagonists/inverse agonists, anti-depressants, and atypicalantipsychotics. For this study, the primary NMDA receptor antagonistused was D-cycloserine (DCS).

Methods: All studies were performed at PsychoGenics, Inc., headquarteredat 765 Old Saw Mill River Road, Tarrytown, N.Y. using an elevated plusmaze (EPM) apparatus to assess behavioral effects of medication.

Preparation: Male C57BI/6J mice from Jackson Laboratories (Bar Harbor,Me.) were used for this study. Mice were received at 6-weeks of age.Upon receipt, mice were assigned unique identification numbers (tailmarked) and were group housed with 4 mice/cage in OPTI mouse ventilatedcages. All animals remained housed in groups of four during theremainder of the study. All mice were acclimated to the colony room forat least 1 week prior to testing and were subsequently tested at anaverage of 7 weeks of age

During the period of acclimation, mice were examined on a regular basis,handled, and weighed to assure adequate health and suitability. Animalswere maintained on a 12/12 light/dark cycle; testing was performedduring the light phase. The room temperature was maintained between 20and 23° C. with a relative humidity maintained between 30% and 70%. Chowand water were provided ad libitum for the duration of the study. Ineach test, animals were randomly assigned across treatment groups. Allanimals were euthanized after the completion of the study.

Apparatus: The elevated plus maze test assessed anxiety. The maze(Kinder Scientific; Poway, Calif.) consists of two closed arms (14.5 cmh×5 cm w×35 cm l) and two open arms (6 cm w×35 cm l) forming a cross,with a square center platform (6×6 cm). All visible surfaces are made ofblack acrylic. Each arm of the maze was placed on a support column 56 cmabove the floor. Antistatic black vinyl curtains (7′ high) surround theEPM to make a 5′ w×5′ l enclosure. Animals were allowed to acclimate tothe experimental room at least 1 hr before the test. Mice were placed inthe center of the elevated plus maze facing the closed arm for a 5-minrun. All animals were tested once. The time spent, distance traveled,and entries in each arm were automatically recorded by the computer. TheEPM was thoroughly cleaned after each test.

Medications: Medications were administered by ip injection. Allmedications were dissolved in appropriate vehicle. Doses are expressedin milligrams per kilogram (mpk).

Statistical analysis. The primary dependent measure for this studyconsisted of % of time spent within the open arms, which is considered ameasure of anti-anxiety effects. Between-condition comparisons wereperformed using post-hoc LSD with one-tailed significance of p<05.

Results: Specific effects of NMDA receptor antagonists onanxiety/akathisia related symptoms were assessed using the measure %time in open arms, which measures willingness to enter an exposed vs.enclosed section of the EPM. Because it represents a ratio betweenactivity in open and closed arms, it is relatively insensitive tochanges in overall activity levels. Potential non-specific effects wereassessed using the total distance traveled, which is a measure ofoverall activation. Locomotor hyperactivity induced by NMDA antagonistsis considered a rodent model of psychosis. 5-HT2A antagonists are knownto reverse effects of high-affinity NMDAR channel blockers on rodentactivity, reflecting their potential use as anti-psychotics. However, nostudies have previously investigated the ability of competitive NMDARantagonists acting at either the glycine or glutamate sites to reversepotential akathisia-related anxiogenic effects of high affinity 5-HT2Aantagonists, or other compounds such as anti-depressants or atypicalantipsychotics potentially associated with antagonism at 5-HT2Areceptors.

Description of the Results.

The results of the foregoing described experiments are set forth inTable 1. Results of an individual representative experiment are setforth in Table 2 and depicted in FIG. 1.

TABLE 1 % time spent Distance in open arm travelled DOI Dose 5-HT2A NMDAStd. Std. Control DOI antagonist Dose antagonist Dose N Mean Dev. MeanDev. Control 0 — — 10 22.438 14.6418 786.30 68.531 DOI 1 mpk — — 1046.859 22.3661 687.10 108.721 DOI 2 mpk — — 30 37.241 17.7516 678.2096.958 DOI/D- 2 mpk — D-  30 mpk 10 44.598 10.6373 781.50 96.345cycloserine cycloserine DOI/D- 2 mpk — D- 300 mpk 10 48.088 14.9833733.70 76.202 cycloserine cycloserine DOI (2 mpk)+ MDL100907 1 MDL1009070.3 mpk — 10 26.760 17.6137 693.20 69.089 MDL100907 2 mpk MDL100907 0.3mpk — 40 21.938 21.4108 741.70 85.718 MDL100907/ 2 mpk MDL100907 0.3 mpkD-  30 mpk 10 20.807 24.1793 735.10 131.341 D- cycloserine cycloserineMDL100907/ 2 mpk MDL100907 0.3 mpk D- 300 mpk 10 35.828 29.2316 887.10105.288 D- cycloserine cycloserine MDL100907/ 2 mpk MDL100907 0.3 mpkCGS- 10 21.749 19.2252 527.00 139.276 CGS19755 19755 MDL100907/ 2 mpkMDL100907 0.3 mpk D-CPPene 10 31.813 22.6649 727.90 66.527 CPPeneMDL100907/ 2 mpk MDL100907 0.3 mpk CP101606 9 25.122 18.9580 775.00157.463 CP101606 MDL100907/ 2 mpk MDL100907 0.3 mpk GV150526A 11 20.81816.6459 663.55 93.861 GV150526A MDL100907/ 2 mpk MDL100907 0.3 mpkL701324 10 25.980 31.5739 522.90 169.097 L701324 MDL100907/ 2 mpkMDL100907 0.3 mpk PCP  1 mpk 10 14.916 13.6545 792.50 155.336 PCPKetanserin 2 mpk Ketanserin   2 mpk — 10 10.400 11.0660 648.90 161.515Ketanserin/ 2 mpk Ketanserin   2 mpk D- 300 mpk 10 21.390 18.2661 640.8096.388 D- cycloserine cycloserine EMD281014 2 mpk EMD281014  30 mpk — 1023.050 20.7257 628.20 110.375 EMD281014/ 2 mpk EMD281014  30 mpk D- 300mpk 10 27.380 26.7496 541.10 148.073 D- cycloserine cycloserineAntipsychotics Lurasidone 2 mpk Lurasidone   1 mpk — 10 36.020 16.2589715.50 116.712 Lurasidone/ 2 mpk Lurasidone   1 mpk D- 300 mpk 10 53.23017.6298 739.10 91.594 D- cycloserine cycloserine Quetiapine 2 mpkQuetiapine  30 mpk — 10 8.950 10.6937 675.50 116.319 Quetiapine/ 2 mpkQuetiapine  30 mpk D- 300 mpk 10 26.004 28.9504 630.20 140.271 D-cycloserine cycloserine Antidepressants Duloxetine 2 mpk Duloxetine  10mpk D- 300 mpk 10 22.290 30.4841 979.50 181.190 cycloserine Mirtazapine2 mpk Mirtazapine   5 mpk D- 300 mpk 10 25.282 22.3245 764.20 97.790cycloserine Venlafaxine 2 mpk Venlafaxine  16 mpk D- 300 mpk 10 21.14412.0805 928.50 78.921 cycloserine

TABLE 2 Bar No. Condition Mean SEM N 1 PTS-DOI (2 mg/kg) 35.569036.428943 10 2 DCS (30 mg/kg) − 44.59816 3.363823 10 DOI (2 mg/kg) 3 DCS(300 mg/kg) − 48.1 4.7 10 DOI (2 mg/kg) 4 MDL100907 9.553678 2.931169 10(0.3 mg/kg) − DOI (2 mg/kg) 5 MDL100907 (0.3 mg/kg) + 20.8 7.6 10 DCS(30 mg/kg) − DOI (2 mg/kg) 6 MDL100907 (0.3 mg/kg) + 35.8 9.2 10 DCS(300 mg/kg) − DOI (2 mg/kg)

DOI (2 mpk) significantly increased % time spent in open arms saline atdoses of both 1 mpk (p<0.05) and 2 mg (p<0.05) DCS had no significanteffect when added to DOI alone at doses of either 30 mpk or 300 mpk,suggesting absence of non-specific behavioral effects in this assaysystem. DCS (300 mpk) significantly reversed effects of MDL100709(p<0.05), whereas effects of DCS (30 mpk) were non-significant.Furthermore, % time spent in open arms was numerically greater forcombined DCS (300 mpk) and both ketanserin and E D28101 than with eitheragent alone. When analyses were performed within experiment, a highlysignificant effect of D-cycloserine (300 mpk) vs. DOI (2 mpk) andMDL100,907 (0.3 mpk) alone was observed (p<0.01) (FIG. 1).

In the presence of DOI (2 mpk), both the 5-HT2A antagonists/inverseantagonists MDL100907 (p=0.001) and ketanserin (p<0.001) and EMD281014(p<0.05) significantly reduced % time spent in open arms, suggesting asignificant liability for akathisia.

The competitive glutamate site antagonist D-CPPene produced trend levelreversal of effects of MDL100.907 (p<0.1) on % time spent in open arms.Other NMDA receptor antagonists, including CGS19755 and CP101606produced numerical improvement. No significant effect was observed forthe channel site antagonist POP, although the tendency was forexacerbation of effect. Furthermore, % time spent in open arms in thepresence of combined D-cycloserine/DOI/DL100907 was significantlygreater than in the presence of combined PCP/DOI MDL100907 (p<0.05).

In addition to selective 5-HT2A antagonists/inverse agonists, theatypical antipsychotics quetiapine (p<0.001) and lurasidone (p<0.05)also significantly reduced % time in open arms, suggesting a liabilityto induce akathisia. For both quetiapine (p<05) and lurasidone (p<0.05)effects were significantly reversed by DOS 300 mpk.

Finally, three antidepressants—duloxetine, mirtazapine, and venlafaxinewere tested in the presence of D-cycloserine (300 mpk) and DOI (2 mpk).All 3 showed significantly reduced % open arm entries vs. DOI alone,consistent with ability to induce akathisia clinically.

Distance Traveled (DT)

As opposed to % time in open arms. DOI (2 mpk) significantly reducedtotal distance traveled. MDL100907 significantly increased DT vs. DOI (2mpk) alone (p<0.05), and this effect was enhanced (rather than reversed)by D-cycloserine (300 mpk) (p<0.001). Other 5-HT2A and NMDAR antagonistshad inconsistent effects alone and in combination with pattern differentfor that observed for the % time spent in open arm measure, reflectingspecificity of the anti-akathisia effects. As a group, duloxetine,venlafaxine and mirtazapine added to DOI (2 mpk) and D-cycloserine (300mpk) significantly enhanced DT compared to DOI (2 mpk) and D-cycloserine(300 mpk) alone (p<0.05).

Summary

These findings demonstrate an unexpected ability of D-cycloserine, athigh doses, to reverse reductions in % time spent in the open arm of theelevated plus maze induced by 5-HT2A antagonists such as MDL100709,ketanserin or atypical antipsychotics Pro-therapeutic effects were seennot only for D-cycloserine, but also for other NMDA receptor antagonistssuch as D-CPPene, CGS19755 or CP 101606. In contrast, the traditionalchannel blocker PCP worsened performance relative to DCS, suggestingthat agents working at the glutamate or glycine binding sites, or loweraffinity channel blockers, such as GlyX-13, may be superior to higheraffinity non-competitive antagonists such as PCP or MK-O′I. Furthermore,although 5-HT2A antagonists are known to reverse hyperactivity inducedby NMDA channel blockers such as ketamine, MK-801, or PCP, the % openarm measure (which compares distance traveled in open vs. closed arms)corrects for overall changes in activity levels.

Although the present animal models leave open the degree to which thephenomenon observed in rodents is isomorphic with drug-induced akathisiaand/or jitteriness/anxiety syndrome in humans, this issue is immaterialto the claimed invention, which nevertheless shows highly potent andunexpected reversal of anxiogenic properties of 5-HT2A antagonistic andatypical antipsychotic compounds by D-cycloserine and other NMDAreceptor antagonists. These findings thus suggest a unique andunexpected benefit from the addition of NMDA receptor antagonists to5-HT2A antagonists including typical/atypical antagonists andantidepressants, and suggests that undesirable anxiogenic side effectsof these compounds can be minimized by the use of NMDAR antagonists.

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It istherefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

It will be understood by those skilled in the art that various changesin form and details may be made therein without departing from thespirit and scope of the invention as set forth in the appended claims.Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed in the scope of the claims.

All publications, patents, and patent applications mentioned herein arehereby incorporated by reference in their entirety as if each individualpublication or patent was specifically and individually indicated to beincorporated by reference. In case of a conflict between thespecification and an incorporated reference, the specification shallcontrol. Where number ranges are given in this document, endpoints areincluded within the range unless otherwise specified. Furthermore, it isto be understood that unless otherwise indicated or otherwise evidentfrom the context and understanding of one of ordinary skill in the artvalues that are expressed as ranges can assume any specific value orsubrange within the stated ranges, optionally including or excludingeither or both endpoints, in different embodiments of the invention, tothe tenth of the unit of the lower limit of the range, unless thecontext clearly dictates otherwise. Where a percentage is recited inreference to a value that intrinsically has units that are wholenumbers, any resulting fraction may be rounded to the nearest wholenumber.

In the claims articles such as “a,”, “an” and “the” mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” or “and/or” betweenmembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in. or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention also includes embodiments in which more than one or all of thegroup members are present in, employed in. or otherwise relevant to agiven product or process. Furthermore, it is to be understood that theinvention provides, in various embodiments, all variations,combinations, and permutations in which one or more limitations,elements, clauses, descriptive terms, etc., from one or more of thelisted claims is introduced into another claim dependent on the samebase claim unless otherwise indicated or unless it would be evident toone of ordinary skill in the art that a contradiction or inconsistencywould arise. Where elements are presented as lists, e.g. in Markushgroup format or the like, it is to be understood that each subgroup ofthe elements is also disclosed, and any element(s) can be removed fromthe group. It should it be understood that, in general, where theinvention, or aspects of the invention, is/are referred to as comprisingparticular elements, features, etc., certain embodiments of theinvention or aspects of the invention consist, or consist essentially ofsuch elements, features, etc. For purposes of simplicity thoseembodiments have not in every case been specifically set forth in haecverba herein. Certain claims are presented in dependent form for thesake of convenience, but Applicant reserves the right to rewrite anydependent claim in independent format to include the elements orlimitations of the independent claim and any other claim(s) on whichsuch claim depends, and such rewritten claim is to be consideredequivalent in all respects to the dependent claim in whatever form it isin (either amended or unamended) prior to being rewritten in independentformat.

I claim:
 1. A method for reducing akathisia caused by lurasidone treatment in a subject with bipolar disorder, comprising: administering an akathisia-inducing amount of lurasidone to the subject; once akathisia is induced, continuing to administer lurasidone at a same dosage and frequency that caused akathisia; and administering a therapeutically effective amount of a second composition comprising D-cycloserine (DCS) at a dosage in excess of 500 mg/day, wherein the DCS produces a NMDA receptor antagonistic blood plasma concentration measured at greater than 25 micrograms/mL, thereby reducing akathisia.
 2. A method for reducing the incidence of akathisia caused by lurasidone treatment in a subject with bipolar disorder, comprising: administering therapeutically effective amounts of lurasidone, ketamine, and D-cycloserine (DCS) to a subject with bipolar disorder, wherein DCS is administered at a dosage in excess of 500 mg/day, wherein the DCS produces a NMDA receptor antagonistic blood plasma concentration measured at greater than 25 micrograms/mL, thereby reducing the incidence of akathisia caused by lurasidone.
 3. The method of claim 1, wherein the lurasidone and second composition are administered intramuscularly, intravenously, intraperitoneally, parentally, or orally.
 4. The method of claim 2, wherein the lurasidone, ketamine, and D-cycloserine (DCS) are administered intramuscularly, intravenously, intraperitoneally, parentally, or orally.
 5. The method of claim 1, wherein the wherein the lurasidone and second composition are formulated as a single composition for administration to the subject.
 6. The method of claim 2, wherein the wherein the lurasidone, ketamine, and D-cycloserine (DCS) are formulated as a single composition for administration to the subject. 